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Flufenamic Acid Prevents Behavioral Manifestations of Salicylate-Induced Tinnitus in the Rat

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Flufenamic Acid Prevents Behavioral Manifestations of Salicylate-Induced Tinnitus in the Rat Experimental research Flufenamic acid prevents behavioral manifestations of salicylate-induced tinnitus in the rat Ramazan Bal1, Yasemin Ustundag2, Funda Bulut3, Caner Feyzi Demir4, Ali Bal5 1Department of Physiology, Faculty of Medicine, Gaziantep University, Gaziantep, Corresponding author: Turkey Prof. Dr. Ramazan Bal 2Department of Anatomy, Faculty of Veterinary, Firat University, Elazig, Turkey Department of Physiology 3Department of Medical Biology, Faculty of Medicine, Kirikkale University, Kirikkale, Faculty of Medicine Turkey Gaziantep University 4Department of Neurology, Faculty of Medicine, Firat University, Elazig, Turkey 27310 Gaziantep, Turkey 5Department of Plastic-Reconstructive and Esthetic Surgery, Faculty of Medicine, Phone: +90 342 Firat University, Elazig, Turkey 3606060/77732 Fax: +90 342 360 16 17 Submitted: 7 March 2014 E-mail: [email protected], Accepted: 21 May 2014 [email protected] Arch Med Sci 2016; 12, 1: 208–215 DOI: 10.5114/aoms.2016.57597 Copyright © 2016 Termedia & Banach Abstract Introduction: Tinnitus is defined as a phantom auditory sensation, the per- ception of sound in the absence of external acoustic stimulation. Given that flufenamic acid (FFA) blocks TRPM2 cation channels, resulting in reduced neuronal excitability, we aimed to investigate whether FFA suppresses the behavioral manifestation of sodium salicylate (SSA)-induced tinnitus in rats. Material and methods: Tinnitus was evaluated using a conditioned lick sup- pression model of behavioral testing. Thirty-one Wistar rats, randomly di- vided into four treatment groups, were trained and tested in the behavioral experiment: (1) control group: DMSO + saline (n = 6), (2) SSA group: DMSO + SSA (n = 6), (3) FFA group: FFA (66 mg/kg bw) + saline (n = 9), (4) FFA + SSA group: FFA (66 mg/kg bw) + SSA (400 mg/kg bw) (n = 10). Localization of TRPM2 to the plasma membrane of cochlear nucleus neurons was demon- strated by confocal microscopy. Results: Pavlovian training resulted in strong suppression of licking, having a mean value of 0.05 ±0.03 on extinction day 1, which is below the suppres- sion training criterion level of 0.20 in control tinnitus animals. The suppres- sion rate for rats having both FFA (66 mg/kg bw) and SSA (400 mg/kg bw) injections was significantly lower than that for the rats having SSA injections (p < 0.01). Conclusions: We suggest that SSA-induced tinnitus could possibly be prevent- ed by administration of a TRPM2 ion channel antagonist, FFA at 66 mg/kg bw. Key words: tinnitus, salicylate, flufenamic acid, TRPM2, experimental, rat. Introduction Tinnitus is defined as a condition or phantom sensation rather than a disease, which is perceived as roaring, buzzing, hissing, whistling and ringing in the ear, due to altered spontaneous neural activity without an external acoustic stimulus [1, 2]. It is usually a consequence of drug toxicity or acoustic trauma [3–6]. It is estimated that 5–15% of the gen- eral population and western population experience this condition [1, 7]. Extending from intermittent form to persistent form, tinnitus changes the quality of daily life. Its effect ranges from a minor to a major influ- Flufenamic acid prevents behavioral manifestations of salicylate-induced tinnitus in the rat ence, preventing spatial learning and intellectual six and kept at room temperature in a 12 h : 12 h working [7, 8]. Therefore, patients may be led to dark-light cycle schedule. Animals were fed with social isolation because of anxiety, insomnia and a balanced commercial diet (Elazig Food Compa- depression, and even to commit suicide [8]. ny, Elazig, Turkey) ad libitum, but were water de- Flufenamic acid (FFA) is a member of fenamates, prived throughout the behavioral testing period. which are derived from N-phenylanthranilic acid Their weights were measured and recorded daily and in the group of non-steroidal anti inflam- during the experimental period. Approval for the matory drugs [9–11]. Fenamates, including FFA, whole experimental process was obtained from cause inhibition in pain pathways, inflammation Firat University Animal Experimentation Ethics and pyrexia by reducing prostaglandin synthe- Committee. sis and inhibiting cyclooxygenase (COX) enzyme, Thirty-one Wistar rats, randomly divided into especially in the treatment of joint and musculo- four treatment groups, were trained and tested skeletal disorders [9, 11–14]. Additionally, FFA is in the behavioral experiment: (1) control group: known to have an antagonistic effect on TRPM2 DMSO + saline (n = 6), (2) SSA group: DMSO + SSA ion channels [15, 16]. TRPM2 is a Ca2+-permeable, (n = 6), (3) FFA group: FFA (66 mg/kg bw) + saline non-selective member of the transient receptor (n = 9), (4) FFA + SSA group: FFA (66 mg/kg bw) + potential melastatin family of cation channels. SSA (400 mg/kg bw) (n = 10). TRPM2 channels are activated by reactive oxy- gen/nitrogen species (ROS/RNS) and ADP-ribose Drugs (ADPR) [15, 17]. TRPM2 has been shown to be Sodium salicylate and FFA were purchased from highly expressed in the central nervous system Sigma. Sodium salicylate solution was prepared (CNS) including the midbrain [18, 19]. freshly in normal saline solution on the day of The treatment options of tinnitus in clinical administration and was administered subcutane- practice are very limited, although there have been ously at 400 mg/kg (in a 100 mg/ml solution of many drug treatments suggested, including anti- saline). This dose has been shown to evoke be- convulsants, antidepressants, GABAergic and an- havioral manifestation of tinnitus [25]. Sodium tiglutamatergic agents, antidopaminergic agents, salicylate or saline was injected 2 h before the and antiepileptic drugs, as reviewed by Langguth testing session. Flufenamic acid was dissolved as and Salvi [5], Fioretti and Eibenstein [6], and Noble a 1 M sol in dimethyl sulfoxide (DMSO), and FFA [20]. Deep brain stimulation [21], as in the case of or vehicle (DMSO) was injected intraperitoneally epilepsy [22], has also been reported to give some 5 h before the testing session. In order to deter- relief. But they, contrary to their claims, are not mine the doses of FFA to be tested, a pilot study used in clinics, since the FDA has not approved any was first conducted in untrained animals, which of these therapeutic approaches to treat tinnitus. were deprived of water for 18 h (n = 6). Flufenamic Because tinnitus is commonly thought to be acid at 66 mg/kg bw had no apparent effects on associated with hyperexcitability of neurons in their movements, feeding and drinking behavior, the central auditory system, including the cochle- alertness and sustained attention to the environ- ar nucleus (CN), the inferior colliculus and the au- ment. This dosage of FFA constitutes an appropri- ditory cortex [12, 23, 24], blocking TRPM2 cation ate concentration of FFA in body fluids for block- channels by administering FFA would modulate age of TRPM2 channels. neural activity of the neurons in the central audi- tory pathway, resulting in a decrease of the neu- Conditioning chamber ronal excitability in auditory nuclei. The decreased neural excitability, in turn, is expected to suppress Training and assessment of each subject was behavioral signs of tinnitus. conducted in the same chamber for all sessions, Therefore, we aimed to investigate the effects which were conducted at the same time each of FFA as a blocker of TRPM2 cation channels in day. Assessment of tinnitus was carried out in a sodium salicylate (SSA)-induced tinnitus animal a homemade conditioning system. The condition- model. ing chamber (40 cm × 30 cm × 45 cm) was housed in a sound-attenuating surrounding box (80 cm Material and methods × 45 cm × 60 cm, minimal attenuation of 45 dB at 10 kHz). The conditioning system consisted Animals of a tungsten bar floored cage, sound generator, Thirty-one healthy adult female Wistar albino camera, apparatus for producing electric shocks rats, aged 8–9 weeks and with weight in the range and remote controls for sound and electric shock of 180–210 g, were obtained from and maintained generators, and a computer. Videos were recorded in Firat University Experimental Research Centre by a camera (Microsoft, HD5000) which was lo- (Elazig, Turkey). They were housed in groups of cated on the most appropriate position at the left Arch Med Sci 1, February / 2016 209 Ramazan Bal, Yasemin Ustundag, Funda Bulut, Caner Feyzi Demir, Ali Bal side of the cage. A drinking bottle was positioned offset of background noise was coupled with elec- 5 cm above the floor, which can be seen best by trical foot shocks (unconditioned stimulus, US). the camera positioned at the left hand side of the After 5 sessions, animals learned well the asso- cage. The illumination of the system was provided ciation between the offsetting of the background by a house light, which was placed on the ceiling sound and foot shocks, and therefore in response of the cage. The house lights within the cham- to offset of the background sound the animals ber were low-wattage bulbs, so there were no stopped licking, namely drinking water. When the audible background sounds in the chamber due suppression rate (SR) falls below 0.2, the lick sup- to the illumination. The current shock stimuli for pression phase is considered to be established Pavlovian conditioning training was generated by [25]. After lick suppression was established, the a constant current shock source (0.5 mA, 1 s) and animals were subjected to the extinction protocol delivered by tungsten bars (4 mm) which were with one trial per day for 4 days using the same lined on the floor with 1.0 cm spaces. A pure tone procedure as in the Pavlovian suppression train- (10 kHz, 65 dB) was turned on before placing the ing, for which no foot shock was delivered during animal in the conditioning chamber and delivered 30 s offset of background noise. during the 30-min testing session. The sound was For tinnitus induction, the animals were given delivered to the conditioning chamber by a speak- a single injection of SSA (400 mg/kg, sc).
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